title: Post-transcriptional regulation of cyclins D1, D3 and G1 and proliferation of human cancer cells depend on IMP-3 nuclear localization.
abstract: RNA-binding proteins of the IMP family (insulin-like growth factor 2 (IGF2) mRNA-binding proteins 1-3) are important post-transcriptional regulators of gene expression. Multiple studies have linked high expression of IMP proteins, and especially of IMP-3, to an unfavorable prognosis in numerous types of cancer. The specific importance of IMP-3 for cancer transformation remains poorly understood. We here show that all three IMPs can directly bind the mRNAs of cyclins D1, D3 and G1 (CCND1, D3 and G1) in vivo and in vitro, and yet only IMP-3 regulates the expression of these cyclins in a significant manner in six human cancer cell lines of different origins. In the absence of IMP-3, the levels of CCND1, D3 and G1 proteins fall dramatically, and the cells accumulate in the G1 phase of the cell cycle, leading to almost complete proliferation arrest. Our results show that, compared with IMP-1 and IMP-2, IMP-3 is enriched in the nucleus, where it binds the transcripts of CCND1, D3 and G1. The nuclear localization of IMP-3 depends on its protein partner HNRNPM and is indispensable for the post-transcriptional regulation of expression of the cyclins. Cytoplasmic retention of IMP-3 and HNRNPM in human cancer cells leads to significant drop in proliferation. In conclusion, a nuclear IMP-3-HNRNPM complex is important for the efficient synthesis of CCND1, D3 and G1 and for the proliferation of human cancer cells.
authors.affiliation: 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France.
authors.forename: T
authors.initials: T
authors.lastname: Rivera Vargas
authors.affiliation: 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France [4] Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Boudoukha
authors.affiliation: 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France.
authors.forename: A
authors.initials: A
authors.lastname: Simon
authors.affiliation: 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France.
authors.forename: M
authors.initials: M
authors.lastname: Souidi
authors.affiliation: Inserm U1016, Institut Cochin, Département Génétique et Développement, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Cuvellier
authors.affiliation: 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France.
authors.forename: G
authors.initials: G
authors.lastname: Pinna
authors.affiliation: 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France.
authors.forename: A
authors.initials: A
authors.lastname: Polesskaya
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics*; D056743:Cyclin D3 / Q000235:genetics*; D056766:Cyclin G1 / Q000235:genetics*; D005786:Gene Expression Regulation; D034761:Heterogeneous-Nuclear Ribonucleoprotein Group M / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D056743:Cyclin D3; D056766:Cyclin G1; C440104:HNRNPM protein, human; D034761:Heterogeneous-Nuclear Ribonucleoprotein Group M; C498780:IGF2BP3 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D019938:Cyclin D1